Successful infection of a host requires that the invading pathogen control production of its virulence determinants. The infectious agent must sense its environment, then respond by increasing production of appropriate factors and repressing production of unnecessary ones. These features are especially critical for vector-borne pathogens, which must not only efficiently infect two extremely different host types, but also be transmitted back and forth between hosts. Deciphering the regulatory pathways used by pathogens to control production of infection-associated proteins will provide significant insight into the infectious nature of those organisms. Moreover, regulatory pathways are attractive candidates for development of novel preventative and curative therapies. We discovered that the Lyme disease spirochete, Borrelia burgdorferi, utilizes a site-specific DNA-binding protein named EbfC to regulate expression of over 50 different genes (>5% of its genome). The EbfC regulon includes genes known to be differentially expressed during the bacteria's infectious cycle, and to be associated with mammalian infection. We hypothesize that EbfC is critical for global regulation of bacterial gene expression, and that dysregulation of the EbfC regulon will prevent efficient mammalian infection. To address that hypothesis, we will critically examine the effects of EbfC on all aspects of the borrelial mammal-tick infectious cycle The vast majority of other bacteria species, including many pathogens, encode homologs of EbfC. Almost nothing is known about those other bacteria's homologs, so our studies will have impacts upon almost the entire domain Eubacteria. Thus, our continued studies will focus efforts toward production of improved preventative and curative therapies for not only Lyme disease, but also many other significant human infectious diseases.